CN105263508B - 治疗和预防缺血性损伤的组合物 - Google Patents
治疗和预防缺血性损伤的组合物 Download PDFInfo
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- CN105263508B CN105263508B CN201480031495.2A CN201480031495A CN105263508B CN 105263508 B CN105263508 B CN 105263508B CN 201480031495 A CN201480031495 A CN 201480031495A CN 105263508 B CN105263508 B CN 105263508B
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Abstract
本发明涉及一种用于治疗和预防缺血性损伤的组合物。更具体而言,本发明涉及一种含有端粒酶衍生肽的组合物,该组合物对治疗和预防缺血性损伤有效。具有本发明序列ID编号所示序列的肽、与所述序列具有80%或以上序列同源性的肽或肽片段对治疗和预防缺血性损伤具有优良效果。因此,含有本发明肽的组合物可有效用于缺血性损伤,尤其是用于缺血性‑再灌注损伤。
Description
技术领域
本发明涉及一种用于治疗和预防缺血性损伤的组合物。更具体而言,本发明涉及一种含有衍生自端粒酶的肽的组合物,该组合物对治疗和预防缺血性损伤有效。
背景技术
缺血性损伤是指由于对需要供血的器官(诸如心脏、脑部、肾脏等)限制供血所引发的组织损伤(心肌梗塞、脑梗塞、肾梗塞等),可导致器官的功能障碍和死亡率上升。缺血性损伤引发心脏、脑部、肾脏等的致命性并发症,增加了器官移植的急性排异反应风险,且长期而言降低了移植器官的存活率。
由于缺血造成的实质供氧不足诱发一种称为缺氧的病理状况。长时间的缺血及缺氧可导致组织的功能丧失,甚至细胞死亡。各种自发及医源性病理状况诱发缺血及缺氧。非限制性实例包括血管阻塞疾病、冠状动脉血栓、脑血管血栓、动脉瘤破裂、全身性出血、挤压损伤、败血症、重度皮肤烧伤、血管结扎术(例如,胸腹动脉瘤手术后的脊髓缺血)、心肺转流术、器官移植、心肺衰竭(心源性猝死)、窒息等。
大体而言,通过增加全身性供氧或移除血管闭塞的原因可将供血及供氧恢复至正常水平,从而治疗由此引发的缺血及缺氧。当与长时间缺血或缺氧的情况相比时,预计可通过恢复供血获得改善结果。然而,在恢复供血及供氧期间,除缺血或缺氧所引发的损伤外,可另外诱发细胞死亡或功能丧失。
恢复供血及供氧期间所诱发的额外损伤称为再灌注损伤。由再灌注损伤所引发的看似反常的组织损伤似乎与由炎性细胞附着至再灌注的组织、炎性细胞的活化及自由基的后续产生所引起的急性发炎症状类似[Granger等人,Ann.Rev.Physiol.,57, 311-332,(1995)]。再灌注的组织内的自由基及其它细胞毒性生物分子的产生可通过坏死或凋亡路径的激活而诱发细胞死亡。
器官移植期间发生的缺血-再灌注(Ischemic-reperfusion;IR)组织损伤导致在器官移植后器官功能的延缓恢复,并且此情况由于炎性组织反应通常是长期维护移植器官功能的过程中不合需要的预后标志。伴随器官(尤其是肾脏)移植偶发的初期缺血-再灌注损伤可导致后续器官衰竭及移植排异反应。
最近,已将肾缺血-再灌注损伤(ischemic-reperfusion injury;IRI)新确认为一种急性炎症反应,其中涉及先天性免疫系统及后天性免疫系统两者的炎性细胞。
皮瓣是指取自身体的一个部位并移动至另一部位的皮肤或组织,其包括可使组织存活的血管。皮瓣手术用于不可通过(例如)植皮治疗的软组织丧失、慢性创口等。此为整形与重建手术中最常用的外科方法。具体而言,其优点在于通过移植包括骨骼、腱、肌肉、神经等在内的各种复合组织可以进行一期重建(primary reconstruction),从而允许快速恢复。在皮瓣手术中,皮瓣的存活率对于缺血-再灌注损伤的治疗至关重要。因此,稳定改善皮瓣存活率的方法将非常有用。
如上所述,用于治疗经常发生的缺血-再灌注损伤的有效方法并不容易获得。因此,预防及治疗缺血-再灌注损伤的有效方法将很有价值。
发明内容
技术问题
本公开的发明人努力开发对治疗和预防缺血-再灌注损伤有效的组合物,并已完成本发明。
本公开的发明人已发现,衍生自端粒酶的肽对治疗和预防缺血-再灌注损伤可具有优良效果。
本发明系针对提供一种对治疗和预防缺血-再灌注损伤有效的组合物。
技术方案
在一方面,本公开提供一种用于治疗和预防缺血性损伤的组合物,该组合物包含:含有SEQ ID NO.1所示氨基酸序列的肽、与所述氨基酸序列具有80%或以上序列同源性的肽或系上述肽的片段。
在本发明的示例性实施方式中,所述片段可包括三个以上氨基酸。
在本发明的示例性实施方式中,所述缺血性损伤可由选自以下的一种或多种引发:缺血-再灌注损伤、血管疾病、冠状动脉血栓、脑血管血栓、动脉瘤破裂、全身性出血、挤压损伤、败血症、皮肤烧伤、血管结扎手术、心肺转流术、器官移植、心肺衰竭(心源性猝死)及窒息。
在本发明的示例性实施方式中,缺血性损伤可由缺血-再灌注损伤引发。
在本发明的示例性实施方式中,缺血-再灌注损伤可选自由以下组成的组:脑血管缺血-再灌注损伤、肾缺血-再灌注损伤、肝缺血-再灌注损伤、缺血-再灌注心肌症、缺血-再灌注皮肤损伤、肠胃缺血-再灌注损伤、肠道缺血-再灌注损伤、胃缺血-再灌注损伤、缺血-再灌注肺损伤、胰腺缺血-再灌注损伤、缺血-再灌注骨骼肌损伤、缺血-再灌注腹肌损伤、缺血-再灌注肢损伤、缺血-再灌注结肠炎、肠系膜缺血-再灌注损伤及无症状缺血-再灌注损伤。
在本发明的示例性实施方式中,缺血-再灌注损伤可由器官移植引发。
在本发明的示例性实施方式中,缺血-再灌注损伤可在肾脏中发生。
在本发明的示例性实施方式中,缺血-再灌注损伤可在皮瓣中发生。
在本发明的示例性实施方式中,肽可衍生自人类端粒酶。
在本发明的示例性实施方式中,组合物可为药物组合物。
在本发明的示例性实施方式中,组合物可为食品组合物。
在另一方面,本发明提供一种用于治疗和预防缺血性损伤的方法,该方法包括:将上文所描述的组合物施用于有需要的受试者。
有益效果
包含SEQ ID NO.1所示氨基酸序列的肽、与该氨基酸序列具有80%或以上序列同源性的肽或上述肽的片段对治疗和预防缺血性损伤具有优良效果。因此,含有所述肽的组合物可有效用于缺血性损伤,尤其是由器官移植等引发的缺血-再灌注损伤。
附图说明
图1图示在缺血-再灌注24小时后测量血尿素氮(blood urea nitrogen;BUN) 及肌酸水平的结果。
图2图示在缺血-再灌注24小时后用过碘酸-希夫氏(periodic acid-Schiff;PAS)染色剂对肾组织染色的结果。
图3图示在缺血-再灌注24小时后实施肾组织损伤计分的结果。
图4图示在缺血-再灌注24小时后用TUNEL染色剂对肾组织染色的结果。
图5图示在缺血-再灌注24小时后测量用TUNEL染色剂所染色的TUNEL阳性细胞的结果。
图6图示在缺血-再灌注24小时后通过用F4/80(巨噬细胞标记物)及Gr-1(嗜中性粒细胞标记物)对肾组织进行免疫组织学染色,从而评估先天性免疫细胞的浸润的结果。
图7图示在缺血-再灌注24小时后测量肾组织中的F4/80(巨噬细胞标记物)及 Gr-1(嗜中性粒细胞标记物)阳性细胞的结果。
图8至图10图示在缺血-再灌注24小时后肾组织中炎性细胞因子的受抑制的分泌。
图11图示用于评估皮瓣存活率的诱发缺血-再灌注损伤的程序。
图12图示在诱发缺血-再灌注7天后PEP1处理组及盐水处理组的皮瓣存活率的测量结果。
图13图示使用ImageJ程序所获得的数字图像。
具体实施方式
可以以各种方式修改及体现本发明。在下文中,将经由示例性实施方式更详细描述本发明。然而,以下实例不欲限制本发明。确切而言,本发明可基于所附权利要求作出各种改变。应理解,本发明包括落入本发明的技术构思及范围内的任何改变、等效物或替代方式。在描述中,可忽略公知特征及技术的细节以避免不必要地模糊所呈现的实施方式。
端粒已知为染色体的末端处所发现的遗传物质的重复序列,用于防止染色体遭受损坏或合并至其它染色体上。每次细胞分裂时,端粒的长度缩短,且在若干次细胞分裂后,端粒长度极度缩短以至于达到细胞停止分裂并死亡的程度。另一方面,已知延长端粒可延伸细胞的寿命。举例而言,癌细胞分泌一种称为端粒酶的酶,端粒酶防止端粒缩短,从而导致癌细胞增生。本发明的发明人已发现,衍生自端粒酶的肽对治疗和预防缺血-再灌注损伤有效,并已完成本发明。
在本发明的示例性实施方式中,SEQ ID NO.1的肽、作为SEQ ID NO.1的肽的片段的肽、或与所述肽具有80%或以上序列同源性的肽包括衍生自端粒酶(特别是,人类(智人)端粒酶)的肽。
本文所揭示的肽可包括:包含与SEQ ID NO.1肽具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%序列同源性的氨基酸序列的肽,或其片段。此外,本发明所揭示的肽可包括:与SEQ ID NO.1的肽或其片段有至少1个氨基酸、至少2个氨基酸、至少3个氨基酸、至少4个氨基酸、至少5个转化氨基酸、至少6个转化氨基酸或至少7个氨基酸不同的肽。
在本发明的一个实施方式中,氨基酸的改变包括肽的物理及化学特性的修饰。举例而言,可进行氨基酸修饰以便改善肽的热稳定性、改变底物特异性及改变最佳pH。
本文中的术语“氨基酸“不仅包括天然整合至肽中的22种标准氨基酸,而且包括D-异构体及修饰氨基酸。因此,在本发明的一特定实施方式中,本文中的肽包括具有D-氨基酸的肽。另一方面,肽可包括非标准氨基酸,诸如翻译后修饰的那些氨基酸。翻译后修饰的实例包括磷酸化、糖基化、酰基化(包括乙酰基化、肉豆蔻酰基化、棕榈酰基化)、烷基化、羧基化、羟基化、糖化、生物素化、泛素化、化学特性的修改(例如,β-移除脱酰亚胺基化、脱酰胺基化)及结构修饰(例如,形成二硫键)。另外,氨基酸的改变包括在与交联剂形成肽共轭物的组合过程期间因化学反应而发生的氨基酸的改变,诸如氨基、羧基或侧链的改变。
本文所揭示的肽可为已从天然来源中鉴定并分离的野生型肽。另一方面,当与SEQID NO.1的肽或其片段相比时,本文所揭示的肽可为人工变异体,该人工变异体包括取代、缺失及/或插入的一个或多个氨基酸。野生型多肽中(不仅在人工变异体中)的氨基酸变化包含蛋白质折叠及/或不明显影响活性的氨基酸的保守取代。保守取代的实例可以在以下各组内:碱性氨基酸(精氨酸、赖氨酸及组氨酸)、酸性氨基酸(谷氨酸及天冬氨酸)、极性氨基酸(谷氨酰胺及天冬酰胺)、疏水氨基酸(亮氨酸、异亮氨酸、缬氨酸及甲硫氨酸)、芳香族氨基酸(苯丙氨酸、色氨酸及酪氨酸) 及小氨基酸(甘氨酸、丙氨酸、丝氨酸及苏氨酸)。大体不改变特定活性的氨基酸取代是本领域中已知的。最常发生的变化为Ala/Ser、Val/Ile、Asp/Glu、Thr/Ser、 Ala/Gly、Ala/Thr、Ser/Asn、Ala/Val、Ser/Gly、Tyr/Phe、Ala/Pro、Lys/Arg、Asp/Asn、 Leu/Ile、Leu/Val、Ala/Glu、Asp/Gly及上述变化的相反变化。下表1中展示保守取代的其它实例。
【表1】
原氨基酸 | 残基取代的实例 | 优选残基取代 |
Ala(A) | val;leu;ile | Val |
Arg(R) | lys;gln;asn | Lys |
Asn(N) | gln;his;asp,lys;arg | Gln |
Asp(D) | glu;asn | Glu |
Cys(C) | ser;ala | Ser |
Gln(Q) | asn;glu | Asn |
Glu(E) | asp;gln | Asp |
Gly(G) | ala | Ala |
His(H) | asn;gln;lys;arg | Arg |
Ile(I) | leu;val;met;ala;phe;正亮氨酸 | Leu |
Leu(L) | 正亮氨酸;ile;val;met;ala;phe | Ile |
Lys(K) | arg;gln;asn | Arg |
Met(M) | leu;phe;ile | Leu |
Phe(F) | leu;val;ile;ala;tyr | Tyr |
Pro(P) | ala | Ala |
Ser(S) | thr | Thr |
Thr(T) | ser | Ser |
Trp(W) | tyr;phe | Tyr |
Tyr(Y) | trp;phe;thr;ser | Phe |
Val(V) | ile;leu;met;phe;ala;正亮氨酸 | Leu |
按以下功效选择明显不同的取代,进行肽的生物学特性的实质修改:(a)维护取代区域内的多肽主链的结构(诸如片层或螺旋三维结构)的功效,(b)维护目标区域内的分子的电荷或疏水性的功效,或(c)维护侧链大小的功效。通过一般侧链特性将天然残基分成如下组:
疏水性:正亮氨酸、met、ala、val、leu、ile;
中性亲水性:cys、ser、thr;
酸性:asp、glu;
碱性:asn、gln、his、lys、arg;
影响链定向的残基:gly、pro;及
芳香性:trp、tyr、phe。
非保守取代可通过将上述类别的成员与不同类别的成员互换来执行。通常可用丝氨酸取代与维护肽的适当三维结构无关的任何半胱氨酸残基,从而增加了分子的氧化稳定性及防止不适当的交联。反之,可通过向肽添加半胱氨酸键实现稳定性的改善。
肽的另一种类型氨基酸变异体是肽的糖基化模式改变的那些肽。此处术语“改变”是指肽中原有的至少一个糖残基缺失及/或肽中不存在的至少一种糖基化残基的添加。
肽中的糖基化通常为N-连接或O-连接。本文中的“N-连接”指糖残基附接于天冬酰胺残基的侧链。作为三肽序列,天冬酰胺-X-丝氨酸及天冬酰胺-X-苏氨酸(其中 X为除脯氨酸外的任何氨基酸)是将糖残基酶促附接于天冬酰胺侧链的识别序列。因此,当多肽中存在所述三肽序列中的一种时,就产生潜在糖基化位点。“O-连接糖基化”是指将糖N-乙酰半乳糖胺、半乳糖或木糖中的一种附接于羟基氨基酸。羟基氨基酸最典型为丝氨酸或苏氨酸,但也可使用5-羟基脯氨酸或5-羟基赖氨酸。
通过改变氨基酸序列以含有上文所论及的三肽序列,可方便地在肽中添加糖基化位点(用于N-连接糖基化位点)。通过在第一肽序列中添加至少一个丝氨酸或苏氨酸残基、或以这些残基进行取代,就可进行上述改变(用于O-连接糖基化位点)。
在本发明中,“缺血性损伤”是指由于限制供血且因此对需要供血的器官(诸如心脏、脑部、肾脏等)供氧不足而发生的损伤,该缺血性损伤可导致组织的功能障碍及细胞死亡。缺血性损伤的原因包括血管疾病、冠状动脉血栓、脑血管血栓、动脉瘤破裂、全身性出血、挤压损伤、败血症、重度皮肤烧伤、血管结扎术(例如,胸腹动脉瘤手术期间的脊髓缺血)、心肺转流术、器官移植、心肺衰竭(心源性猝死)、窒息等,但并不限于此。
在本发明中,“缺血性损伤”还包括在(例如)器官移植期间可发生的缺血-再灌注损伤。缺血-再灌注损伤包括脑血管缺血-再灌注损伤、肾缺血-再灌注损伤、肝缺血-再灌注损伤、缺血-再灌注心肌症、缺血-再灌注皮肤损伤、肠胃缺血-再灌注损伤、肠道缺血-再灌注损伤、胃缺血-再灌注损伤、缺血-再灌注肺损伤、胰腺缺血- 再灌注损伤、缺血-再灌注骨骼肌损伤、缺血-再灌注腹肌损伤、缺血-再灌注肢损伤、缺血-再灌注结肠炎、肠系膜缺血-再灌注损伤、无症状缺血-再灌注损伤等,但并不限于此。
在器官移植期间可经常发生缺血-再灌注损伤。举例而言,众所周知,移植肾脏的逐渐功能丧失及功能障碍与缺血-再灌注损伤相关,并且由缺血-再灌注组织损伤导致的先天性免疫系统活化是重要原因之一。
具有SEQ ID NO.1所示序列的肽、作为具有SEQ ID NO.1所示序列的肽的片段的肽、或与本公开的肽具有80%或以上序列同源性的肽有利指出在于它们因低毒性而展现出高体内稳定性。SEQ ID NO.1所示的肽衍生自端粒酶、并且由16个氨基酸组成。
SEQ ID NO.1中所描述的肽与下表2中相同。下表2中的“名称”用于区分各肽。在一方面,SEQ ID NO.1的肽是人类端粒酶的完整肽。在本发明的不同特定实施方式中,具有SEQID NO.1所示序列的肽、作为具有SEQ ID NO.1所示序列的肽的片段的肽、或与本发明的肽具有80%或以上序列同源性的肽包括通过选择及合成对应于端粒酶内的相关位置的肽而合成的“合成肽”。SEQ ID NO.2是完整端粒酶的氨基酸序列。
【表2】
在一方面,本发明提供一种用于治疗和预防缺血性损伤的组合物,该组合物包含作为活性成分的含有SEQ ID NO.1所示氨基酸序列的肽、与所述氨基酸序列具有80%或以上序列同源性的肽、或上述肽的片段。
在本发明的一个实施方式中,组合物可含有0.1μg/mg至1mg/mg,特定而言 1μg/mg至0.5mg/mg,更具体而言10μg/mg至0.1mg/mg的含有SEQ ID NO.1 中至少一种氨基酸序列的肽、含有与上述序列具有至少80%序列同源性的氨基酸序列的肽、或上述肽的片段。当含有上述范围内的所述肽时,可同时满足组合物的安全性及稳定性,且该范围在成本效益方面适宜。
在本发明的一个实施方式中,组合物可应用于包括人、犬、鸡、猪、奶牛、绵羊、豚鼠及猴在内的所有动物。
在示例性实施方式中,本发明提供一种用于治疗和预防缺血-再灌注损伤的药物组合物,该组合物包含:含有SEQ ID NO.1所示氨基酸序列的肽、与该氨基酸序列具有80%或以上序列同源性的肽、或所述肽的片段作为活性成分。
在本发明的一个实施方式中,可经由口服、直肠、经皮、静脉内、肌内、腹膜内、骨髓内、硬膜外或皮下路径施用药物组合物。
口服给药的形式可为(但不限于)片剂、丸剂、软胶囊或硬胶囊、颗粒剂、粉末剂、溶液或乳液。非口服给药的形式可为(但不限于)注射、滴剂、洗液、软膏剂、凝胶剂、乳膏剂、悬浮液、乳液、栓剂、贴片或喷雾。
在本发明的一个实施方式中,药物组合物必要时可含有添加剂,诸如稀释剂、赋形剂、润滑剂、粘合剂、崩解剂、缓冲剂、分散剂、表面活性剂、着色剂、芳香剂或甜味剂。在本发明的一个实施方式中,药物组合物可由本领域中的常规工业方法制造。
在本发明的一个实施方式中,药物组合物的活性成分的剂量可根据患者年龄、性别、体重、病理及状态、给药路径或处方医师的诊断而变化。基于这些因素的剂量可在本领域技术人员的水平内决定,每日剂量(例如)可为(但不限于)0.1μg/kg/ 日至1g/kg/日,特定而言1μg/kg/日至10mg/kg/日,更特别10μg/kg/日至 1mg/kg/日,更特别50μg/kg/日至100μg/kg/日。在本发明的一个实施方式中,每日可施用药物组合物1至3次,但不限于此。
在示例性实施方式中,本发明提供一种用于治疗和预防缺血-再灌注损伤的食品组合物,该组合物包含:含有SEQ ID NO.1所示氨基酸序列的肽、与所述氨基酸序列具有80%或以上序列同源性的肽、或上述肽的片段作为活性成分。
在本发明的一个实施方式中,食品组合物不限于特定形式,但(例如)可为片剂、颗粒剂、粉末剂、液体及固体形式。形成各形式的除活性成分外还可有由本领域技术人员适当选择的工业中常用的成分,且它们与其它成分组合可产生协同效应。
上述活性成分剂量的决定处于本领域技术人员的水平内,且每日剂量(例如)可为1μg/kg/日至10mg/kg/日,更特别10μg/kg/日至1mg/kg/日,更特别50μg/kg/ 日至100μg/kg/日,但不限于所述数字,并可根据年龄、健康状态、并发症及其它各种因素而变化。
本文所使用的术语意欲用于描述实施方式,但不欲限制本发明。前面没有数字的术语并不限制量,但展示可存在所使用术语的一个以上的事物。应开放式地解读术语“包含”、“具有”、“包括”及“含有”(亦即,“包括但不限于”)。
论及数值范围,而不陈述范围内的单独数字,因此除非明确指出,否则该范围应将视为本文单独描述的范围内的所有数字。所有范围的末端值包括于该范围内且可独立组合。
除非另作说明或在上下文中明显矛盾,可以以适当次序执行本文所论及的所有方法。除在权利要求中以外,任一实施方式及所有实施方式或示例性语言(例如,“诸如”、“等”)的使用是用于更清楚地描述本发明,而非限制本发明的范围。在本文中的权利要求的任何语言不应解读为本发明必需的。除非另有定义,本文所使用的技术及科学术语具有为本发明所属技术领域技术人员通常所理解的含义。
本发明的优选实施方式方式包括发明人已知的执行实施本发明的最佳模式方式。实施方式中的变化可本领域技术人员在阅读上文陈述后对熟习此项技术者变得可清楚优选实施方式中的变化。本发明人希望本领域技术人员可充分使用变化及,并可以与本文中所列出方式不同的其它方式实施本发明。因此,如专利法所允许,本发明包括随附权利要求中所陈述的本发明的关键点的等效物、修改及变化。另外,除非另有明确陈述或在上下文中矛盾,上文所述组份的任何组合内的所有可能变化皆包括于本发明中。尽管通过示例性实施方式描述及展示了本发明,但是本领域技术人员将充分理解:在不背离由权利要求所限定的本发明精神及范围的情况下,在形式及细节中可存在各种改变。
在以下实例中,通过向肾及腹直肌皮瓣所诱发的缺血-再灌注损伤部分施用肽,并确认抑制肾损伤和改善皮瓣存活性的效果,调查了具有SEQ ID NO.1所示序列的肽 (PEP1)对预防及治疗缺血性损伤的效果。
在下文中,将经由实施例及测试实施例详细描述本发明。然而,以下实施例及测试实施例仅出于说明性目的,且将对本领域技术人员显而易见的是本发明的范围不限于该等实施例及测试实施例。
实施例1:肽的合成
根据固相肽合成的常规已知方法合成SEQ ID NO.1的肽。更具体而言,通过使用ASP48S(Peptron,Inc.,Daejeon ROK)经由Fmoc固相肽合成(solid phase peptidesynthesis;SPPS)从C末端偶联各种氨基酸来合成肽。使用C末端处第一个氨基酸附接于树脂的那些肽,如下所示:
NH2-Lys(Boc)-2-氯-三苯甲基树脂
NH2-Ala-2-氯-三苯甲基树脂
NH2-Arg(Pbf)-2-氯-三苯甲基树脂
在N末端处通过Fmoc保护用于合成肽的所有氨基酸,并通过可溶解于酸的Trt、Boc、t-Bu(t-butylester;叔丁酯)、Pbf(2,2,4,6,7-五甲基二氢-苯并呋喃-5-磺酰基)保护氨基酸残基。实例包括以下:
Fmoc-Ala-OH、Fmoc-Arg(Pbf)-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Pro-OH、
Fmoc-Leu-OH、Fmoc-Ile-OH、Fmoc-Phe-OH、Fmoc-Ser(tBu)-OH、
Fmoc-Thr(tBu)-OH、Fmoc-Lys(Boc)-OH、Fmoc-Gln(Trt)-OH、
Fmoc-Trp(Boc)-OH、Fmoc-Met-OH、Fmoc-Asn(Trt)-OH、Fmoc-Tyr(tBu)-OH、
Fmoc-Ahx-OH、Trt-巯基乙酸。
将HBTU[2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基铵六氟磷酸盐(酯)]/HOBt[N-羟基苯并三唑]/NMM[4-甲基吗啉]用作偶联剂。使用20%DMF中的哌啶移除Fmoc。为了从残基上移除保护或为了从树脂中分离合成肽,使用分解混合液[TFA(三氟乙酸)/TIS(三异丙基硅烷)/EDT(乙二硫醇)/H2O=92.5/2.5/2.5/2.5]。
通过使用固相支架并重复以下过程来进行肽合成:从氨基酸保护开始,各种氨基酸的单独反应,用溶剂洗涤,和脱保护。通过以下方式合成各肽:使用与起始氨基酸结合的固相支架及氨基酸保护,使相应氨基酸单独反应,用溶剂洗涤及脱保护,并重复该过程。在自树脂上释放后,所合成肽通过HPLC纯化、通过质谱分析法确认,并冻干,并且通过MS对合成进行验证,随后冻干。
所制备肽的纯度经高效液相色谱发现为95%以上。
具体肽合成过程基于具有SEQ ID NO.1的PEP 1的合成过程描述如下。
1)偶联
将用NH2-Lys(Boc)-2-氯-三苯甲基树脂保护的氨基酸(8当量)及在DMF中溶融的偶联剂HBTU(8当量)/HOBt(8当量)/NMM(16当量)混合在一起,并在室温(RT) 下温育2小时。在温育后,反应混合物进行DMF、MeOH及DMF的相继洗涤。
2)Fmoc脱保护
添加20%DMF中的哌啶,并在RT下温育5分钟,2次,随后用DMF、MeOH及DMF 相继洗涤。
3)通过重复上述反应1)及2),制成肽的基本构架 NH2-E(OtBu)-A-R(Pbf)-P-A-L-L-T(tBu)-S(tBu)-R(Pbf)L-R(Pbf)-F-I-P-K(Boc)-2- 氯-三苯甲基树脂。
4)切割:将切割混合液添加至完全合成的肽中,由此从树脂上分离所合成的肽。
5)将预先冷却的二乙醚添加至所获得的混合物中,及随后使用离心沉淀所收集的肽。
6)在通过制备型HPLC纯化后,通过LC/MS确认分子量,并经冻干以产生粉末形式。
实施例2:确认PEP1对抑制肾缺血-再灌注损伤模型中的肾损伤的效果
测试实施例1:缺血-再灌注的诱发
在双侧夹紧肾蒂30分钟并在30分钟后通过移除夹具恢复血流,诱发缺血-再灌注,从而建立肾缺血-再灌注损伤小鼠模型。测试组被分成施用组(PEP 1)、对照组(没有PEP 1的PBS)及假手术组(无双侧夹紧)。在诱发缺血-再灌注前的30分钟及诱发缺血-再灌注12小时后以1000nmol/kg的浓度皮下注射PEP 1。
使用C57BL/6小鼠(8周大;Charles River Laboratories,Wilmington,MA) 诱发肾缺血-再灌注损伤。在通过血管钳夹紧肾蒂阻断血流及诱发缺血28分钟后,执行再灌注。
在PBS中稀释肽PEP 1至1000nmol/kg的浓度,并在缺血-再灌注前的30分钟及缺血-再灌注12小时后于腹腔内(i.p.)注射两次。针对施用组(PEP 1)、对照组(PBS) 及假手术组(无缺血-再灌注)实施测试。
测试实施例2:PEP 1对IRI诱发肾衰竭的预防效果
在缺血-再灌注24小时后采集血液并测量血尿素氮(BUN)及肌酸的水平作为肾毒性标记。采集肾组织及制备成石蜡块用于免疫组织化学及组织学研究。随后,提取蛋白并测量细胞因子的水平。使用自动分析器(Technicon RA-1000;Bayer,Tarrytown, NY)测量肌酸及BUN的浓度。
结果是,施用PEP 1组展示出与PBS对照组相比明显减少的BUN及肌酸水平(图 1)。
测试实施例3:PEP 1对预防肾组织损伤的效果
在缺血-再灌注24小时后根据制造商(Polysciences,Inc.,华盛顿,PA,美国) 的规程用过碘酸-希夫氏(PAS)染色剂对肾组织染色。在染色后,经由肾组织损伤计分评估肾组织损伤。施用PEP 1组展示出与PBS对照组相比显著减少的肾组织损伤(图 2及图3)。
测试实施例4:抑制肾细胞凋亡的效果
通过在缺血-再灌注24小时后用TUNEL染色剂对肾组织染色评估肾细胞凋亡。使用TUNEL染色试剂盒(Roche Applied Science,印第安娜波利斯,IN,美国)用TUNEL 对肾石蜡切片染色。
结果是,施用PEP 1组展示出与PBS对照组相比显著减少的TUNEL阳性细胞,表明PEP 1抑制肾组织的细胞死亡(图4及图5)。
测试实施例5:抑制肾组织中的先天性免疫细胞的侵润的效果
在缺血-再灌注24小时后通过用F4/80(巨噬细胞标记物)及Gr-1(嗜中性粒细胞标记物)对肾组织进行免疫组织学染色来评估先天性免疫细胞的浸润。特定而言,使用巨噬细胞特异性抗体(F4/80;Abcam,Cambridge,MA)对石蜡切片中的浸润巨噬细胞及嗜中性粒细胞进行免疫组织学染色。
施用PEP 1组展示出与PBS对照组相比显著减少的巨噬细胞及嗜中性粒细胞对肾组织浸润(图6及图7)。
测试实施例6:抑制炎性细胞因子的分泌的效果
在缺血-再灌注24小时后从肾组织中提取蛋白质并根据流式细胞术微珠阵列法测量IL-6、MCP-1及TNF-α的水平。小鼠IL-6、MCP-1、TNF-αELISA试剂盒购自 R&D Systems,并根据制造商规程实施测试。
结果是,施用PEP 1组展示出与PBS对照组相比明显减少的IL-6及MCP-1水平,但对于TNF-α未观察到明显差异(参看图8至图10)。
如上文所描述,通过测试肾衰竭(BUN及肌酸)、肾组织损伤(肾小管损伤)、肾细胞凋亡、免疫细胞浸润及肾组织中细胞因子分泌,评估了PEP 1对预防肾缺血- 再灌注损伤的效果。
PBS对照组展示出与假手术组相比增加的血清BUN和肌酸水平以及更大的肾组织损伤。相比的下,施用PEP 1组展示出与对照组相比明显减少的BUN和肌酸水平以及减少的肾组织损伤及肾细胞凋亡。而且,施用PEP 1组展示出与PBS对照组相比抑制炎性细胞(嗜中性粒细胞及巨噬细胞)的浸润,并明显抑制肾脏中的炎性细胞因子(白介素-6及单核细胞趋化蛋白-1)的分泌。
实施例3:PEP 1对改善缺血-再灌注损伤模型中的腹直肌肌皮皮瓣存活率的效果
测试实施例1:缺血-再灌注的诱发
从Sprague-Dawley大鼠(体重180-230g)的腹部获得5cm×5cm皮瓣,施用 PEP1或盐水,经由夹紧诱发局部缺血及随后在7小时后通过移除夹具恢复血流,从而建立缺血-再灌注损伤大鼠模型(参看图11)。
测试组被分成施用组(PEP 1)、对照组(没有PEP 1的PBS)及假手术组(未诱发缺血-再灌注损伤)。在诱发缺血-再灌注前的30分钟及诱发缺血-再灌注1、2、3、4、5及7天后肌内注射PEP 1(10mg/500μL)或PBS(500μL)。
测试实施例2:PEP1对改善皮瓣存活率的效果
在诱发缺血-再灌注7天后测量皮瓣存活率。使用imageJ程序分析数字影像测量皮瓣存活率。
结果是,PBS治疗组的皮瓣存活率为34.69%±16.44%,PEP1治疗组展示出58.88%±11.44%的改善的皮瓣存活率(参看图12)。在组间有统计学显著性(p<0.05)。
Claims (9)
1.由SEQ ID NO.1所示氨基酸序列组成的肽在制备用于治疗和预防缺血性损伤的组合物中的应用,其中,所述缺血性损伤由缺血-再灌注损伤引发。
2.如权利要求1所述的应用,其中,所述缺血-再灌注损伤选自由以下组成的组:脑血管缺血-再灌注损伤、肾缺血-再灌注损伤、肝缺血-再灌注损伤、缺血-再灌注心肌症、缺血-再灌注皮肤损伤、肠胃缺血-再灌注损伤、缺血-再灌注肺损伤、胰腺缺血-再灌注损伤、缺血-再灌注骨骼肌损伤、缺血-再灌注腹肌损伤、缺血-再灌注肢损伤、缺血-再灌注结肠炎、肠系膜缺血-再灌注损伤及无症状缺血-再灌注损伤。
3.如权利要求2所述的应用,其中,所述肠胃缺血-再灌注损伤选自由肠道缺血-再灌注损伤和胃缺血-再灌注损伤组成的组。
4.如权利要求1所述的应用,其中,所述缺血-再灌注损伤由器官移植引发。
5.如权利要求1所述的应用,其中,所述缺血-再灌注损伤在肾脏中发生。
6.如权利要求1所述的应用,其中,所述缺血-再灌注损伤在皮瓣中发生。
7.如权利要求6所述的应用,其中,所述组合物用于改善皮瓣的存活率。
8.如权利要求1所述的应用,其中,所述肽衍生自人类端粒酶。
9.如权利要求1所述的应用,其中,所述组合物是药物组合物。
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